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Download (7MB) https://theses.gla.ac.uk/ Theses Digitisation: https://www.gla.ac.uk/myglasgow/research/enlighten/theses/digitisation/ This is a digitised version of the original print thesis. Copyright and moral rights for this work are retained by the author A copy can be downloaded for personal non-commercial research or study, without prior permission or charge This work cannot be reproduced or quoted extensively from without first obtaining permission in writing from the author The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the author When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given Enlighten: Theses https://theses.gla.ac.uk/ [email protected] EFFECTS OF ANTIEPILEPTIC DRUGS IN RODENT AND HUMAN ASTROCYTE CULTURES, RODENT BRAIN AND PENTYLENETETRAZOL-INDUCED SEIZURES IN MICE A thesis by Caroline Margaret Fraser submitted for the degree of Doctor of Philosophy to University of Glasgow from University Department of Medicine and Therapeutics Western Infirmary Glasgow G il 6NT April 1999 i ProQuest Number: 10992148 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a com plete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest ProQuest 10992148 Published by ProQuest LLC(2018). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States C ode Microform Edition © ProQuest LLC. ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106- 1346 Iftlp ABSTRACT There is increasing evidence to suggest that most antiepileptic drugs (AEDs) have multiple mechanisms of action which may contribute to their efficacy and/or toxicity. Of particular current interest is the effects of AEDs on the excitatory and inhibitory amino acid systems regulated by glutamate and y-aminobutyric acid (GABA), respectively. Primary cultures of rat cortical astrocytes were employed to examine the effects of a range of AEDs on the uptake of GABA and glutamate and on the activity of the GABA-metabolizing enzyme GABA-transaminase (GABA-T). One hour exposures to sodium valproate (SVP), vigabatrin (VGB), felbamate (FBM) and tiagabine (TGB) significantly reduced GABA uptake into primary cultures of rat cortical astrocytes over a broad range of concentrations examined. Phenobarbitone (PB), phenytoin (PHT), carbamazepine (CBZ), lamotrigine (LTG), gabapentin (GBP), topiramate (TPM), levetiracetam (LEV) and desglycinyl-remacemide (DGR) were without effect. A one hour exposure to PB resulted in a reduction in glutamate uptake into primary cultures of rat cortical astrocytes with the lowest three concentrations examined, with no effect on glutamate transport at the highest concentrations. TGB and DGR were also found to reduce glutamate uptake, however, the effects appeared to concentration-independent and not evident over the dose range. PHT, CBZ, SVP, VGB, LTG, FBM, GBP, TPM and LEV were without effect. One hour exposures to VGB and DGR consistently reduced the activity of GABA-T in primary cultures of rat cortical astrocytes. SVP and TGB were also found to decrease GABA-T activity, however, the effect was only evident at the highest concentration examined for each of the drugs. PB, PHT, CBZ, LTG, FBM, GBP, TPM and LEV were without effect. Glutamine synthetase (GS) is a key enzyme in the regulation of glutamate neurotransmission in the central nervous system (CNS). The effects of single and repeated intraperitoneal (i.p.) administration of a range of AEDs on GS activity were investigated in mouse brain. Four hours after the final dose the animals were sacrificed and their brains removed for analysis of GS activity. Single doses of PHT and CBZ were found to dose-dependently reduce enzyme activity. Repeated doses of PB, PHT, CBZ, FBM and TPM dose-dependently reduced the activity of GS. SVP, VGB, LTG, GBP, TGB, LEV and DGR were without effect on enzyme activity. In addition, due to the glial location of the enzyme, the effects of a range of AEDs on GS activity were examined in primary cultures of rat cortical astrocytes. A one hour exposure to PB reduced GS activity in primary cultures of rat cortical astrocytes. PHT, CBZ, SVP, VGB, LTG, FBM, GBP, TPM, TGB, LEV and DGR were without effect following a one hour exposure. These results suggest that effects of these AEDs on the transport and metabolism of GABA and glutamate may contribute to the clinical effects of the drugs, and appear to support the observation that many AEDs have multiple mechanisms of action. FBM, TPM and LEV are three new AEDs whose precise mechanism of action remains to be M y elucidated. Each has reported effects on amino acid neurotransmitter systems. In light of this, the effects of single and repeated administration of FBM, TPM and LEV were investigated on GABA- and glutamate-related neurochemistry in mouse brain. Both single and repeated treatments with FBM, TPM and LEV were without significant effect on the concentrations of GABA glutamate and glutamine. Similarly, single and repeated treatments with all three drugs were without significant effect on the activities of GABA-T or glutamic acid decarboxylase (GAD). These results suggest that effects on GABAergic and glutamatergic systems are not involved in the mechanisms of action of these drugs. Approximately 30% of patients with epilepsy do not respond to monotherapy and require treatment with two or more AEDs. However, there is very little scientific or clinical evidence highlighting the efficacy of particular combinations. Three of the new AEDs, LTG, GBP and TPM are commonly used as add-on therapy for refractory partial seizures. The effects of these drugs in single dose and in combination were examined on experimental seizures induced by the chemoconvulsant pentylenetetrazol (PTZ) in mice, in an attempt to identify efficacious combinations of new AEDs. When administered alone, only the highest dose of LTG examined significantly increased the latency to the first PTZ-induced generalised seizure. Both GBP and TPM alone were without effect. Five of the nine combinations of LTG with GBP signficantly increased the seizure latency in mice. In addition, a combination of GBP with TPM was found to have a significant anticonvulsant effect when compared to control. All other combinations of AEDs examined were without effect on PTZ- induced generalised seizures at one hour post-administration. This preliminary study woud suggest that the combination of LTG with GBP, and possibly TPM with GBP, may be an effective polytherapy regimen and require further detailed experimental and clinical investigation. SVP, VGB and TGB were all found to exert effects on the GABAergic system when investigated in primary cultures of rat cortical astrocytes. It was of interest to examine the effects of these drugs on the uptake of GABA into primary cultures of human adult and foetal astrocytes. SVP, VGB and TGB significantly reduced the uptake of GABA into adult human astrocytes in primary culture following a one hour exposure. SVP and VGB also significantly reduced GABA uptake into primary cultures of human foetal astrocytes. However, TGB was without effect in the foetal astrocytes following a one hour exposure. The lack of effect of TGB in the human foetal astrocyte cultures may indicate the incomplete development of the GABA transporter GAT-1 in foetal brair. where TGB is known to act. The reduction in GABA uptake exerted by SVP and VGB in human foetal astrocytes may reflect a different mechanism of action of GABA uptate inhibition from that of TGB, possibly not involving GAT-1. CONTENTS Page TITLE i ABSTRACT ii CONTENTS vi LIST OF FIGURES xvii LIST OF PHOTOGRAPHS xxv LIST OF TABLES xxv DECLARATION xxvii ACKNOWLEDGEMENTS xxviii PUBLICATIONS xxix ABBREVIATIONS xxxii CHAPTER ONE: INTRODUCTION 1 1.1 EPILEPSY 2 1.1.1 Definition of epilepsy 2 1.1.2 Seizure classification 2 1.1.3 Partial (focal, local) seizures 3 1.1.4 Generalised (convulsive or non-convulsive) seizures 4 1.1.5 Other seizure types 4 1.2 NEUROTRANSMITTERS AND EPILEPSY 4 1.2.1 Inhibitory neurotransmission 5 1.2.2 Evidence for the role of GABA in epilepsy 7 1.2.3 Excitatory neurotransmission 8 1.2.4 Evidence for the role of glutamate in epilepsy 9 1.3 ASTROCYTES 10 1.3.1 Types of astrocytes 11 1.3.2 Development of type I and type II astrocytes 12 1.3.3 Role of astrocytes in the central nervous system 13 1.3.4 Functional differences between type I and typeII astrocytes 15 1.3.5 Role of astrocytes in disease 15 1.3.6 Astrocytes and epilepsy 16 1.4 TREATMENT OF EPILEPSY 18 1.4.1 History of antiepileptic drug treatment 18 1.4.2 Strategies for the drug treatment of epilepsy 19 1.4.3 Established antiepileptic drugs 20 1.4.4 Novel antiepileptic drugs 26 1.4.5 Novel antiepileptic drugs undergoing clinical evaluation 34 AIMS 37 CHAPTER TWO: MATERIALS AND METHODS 38 2.1 MATERIALS 39 2.1.1 Chemicals 39 2.1.2 Radioisotopes 40 2.1.3 Antiepileptic drugs 40 2.1.4 Antibodies 41 2.1.5 Animals 41 2.2 REMOVAL AND STORAGE OF BRAIN TISSUE 42 2.3 PRIMARY CULTURE OF RAT CORTICAL ASTROCYTES 42 2.3.1 Culture medium 42 vii 2.3.2 Isolation of cells 43 2.3.3 Culture maintenance 44 2.4 PRIMARY CULTURE OF HUMAN ASTROCYTES FROM 44 FOETAL POST-MORTEM AND ADULT
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